1. Field of the Invention
The present invention relates to certain esters of substituted 3-aminopropane phosphinic acid derivatives. More specifically, the present invention relates to esters of 3-amino-2-propane-cycloalkyl(aryl)methyl phosphinic acid derivatives of formula I. This invention also relates to methods of making these compounds. The compounds of this invention are transformed in vivo into biologically active compounds and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases including diseases associated with the central nervous system.
2. Description of the Art
U.S. Pat. No. 5,190,933 discloses certain substituted propane phosphinic compounds having therapeutic utility in treating various disorders including cognition and memory disorders, anxiety and depression. However, a problem posed by these compounds is their poor bioabsorption. It has also been reported in the literature that certain compounds such as bisphosphonates exhibit poor absorption from the GI tract. In fact, only one percent of the oral dose is absorbed. As a result, a series of peptidyl prodrugs of these bisphosphonates have been made and shown to improve the drug absorption. See, Ezra, et al., J. Med. Chem. 2000, 43, 3641.
Another concern associated with these structural types of compounds is their oral administration. Generally, such compounds result in patient complaints shortly after dosing; said complaints are usually characterized by the patients as heartburn, esophageal burning, pain and/or difficulty upon swallowing, and/or pain existing behind and/or mid-sternum. It is believed that these complaints originate from esophagitis or esophageal irritation caused by the erosion, ulceration, or other like irritation of the epithelial and mucosal tissues of the upper gastrointestinal tract, generally the mouth through the esophagus, most generally the esophagus.
Another concern with these phosphinic acid compounds is that their slow oral absorption due to high polarity thereby lengthening the time to reach maximum concentration in the plasma. As a consequence, the concentration of the compound is also low in the brain. However, in order to have a faster onset of activity it is necessary that the drug substance level in the brain is high.
It has been reported in the literature that phosphonic acids can be derivatized to form prodrugs, wherein a group that can hydrolyze remotely from the phosphorus oxygen bond (distal hydrolysis) was found to provide better pharmacological profiles including better oral absorption and faster onset of action by having higher levels of the drug substance in the plasma.
All of the references described herein are incorporated herein by reference in their entirety.
Accordingly, it is an object of this invention to provide a series of substituted 3-aminopropane phosphinic acid derivatives which hydrolyze readily under physiological conditions and provide improved pharmacological properties
Other objects and further scope of the applicability of the present invention will become apparent from the detailed description that follows.